1. Field of the Invention
The invention is generally related to emergency medicine. In particular, the invention relates to bleeding and bleeding injuries.
2. Background Description
The morbidity and mortality from penetrating injuries (such as ballistic injuries in combat, knife wounds, penetrating wounds secondary to motor vehicle accidents, etc.) has decreased over the past fifty years. However, some undesirable results remain. Present treatments for high pressure, i.e. arterial, bleeding can cause ischemia that might contribute to limb loss. Tourniquet use can contribute to the need for amputation. This is especially true if there is a significant delay in definitive treatment.
As to military trauma, two characteristics of death due to such trauma are seen. First, early death occurs. Soldiers who die due to injury, die early: about 40% die immediately; 25% die within 5 minutes; 15% die within 15 minutes; i.e., a total of 80% dead in the first 15 minutes after trauma. A second feature of military trauma is death due to bleeding, with ⅔ of military deaths due to trauma being due to hemorrhage.
Ballistic injury is a primary mode of trauma in combat. Such injuries can be associated with rapid blood loss due to vascular disruption. In the Vietnam conflict, ten percent of wounds to the extremity were associated with major artery injury. M. E. Jabaley, H. D. Peterson, “Early treatment of war wounds of the hand and forearm in Vietnam,” Ann Surg 1973; 177:167-73. While bleeding from compressible vessels may respond to direct pressure, blood loss from deep muscular branches (such as those from the profunda femoris artery, etc., e.g., see Table 1) may be severe. S. M. Henry, R. Tornetta III, T. M. Scalea, “Damage control for devastating pelvic and extremity injuries,” Surg Clin North Am, 77:879-95 (1997). Despite increasingly aggressive surgical treatment, limb salvage has not improved. P. V. Sharma, S. C. Babu, P. M. Shah, R. H. Clauss, “Changing patterns in civilian arterial injuries,” J. Caridovasc Surg (Torino), 26:7-11 (1985). Death from hemorrhagic shock remains a problem even in very healthy individuals. J. Valentine, S. Blocker, J. H. Chang, “Gunshot injuries in children,” J Trauma, 24:952-6 (1984). As can be appreciated from the following Table 1, combat vascular injuries continue to result in a 12 to 30 percent amputation rate depending on the involved vessel.
TABLE 1(Incidence of major lower extremity vascular injuries in thethree great wars) (Source: Vascular Trauma, Rich N. M. and Spencer,F. C. (eds.), W. B. Sunders, Philadelphia, 1978).TotalCommonExternalCommonDeepSuperficialWarArteriesIliacIliacfemoralFemoralFemoralPoplitealWWI120214366144WWII24711330 106**23517502Korean304 95! 79#Vietnam1000917* 46*** 305@ 217#*three amputations and one death**ligation lead to 86 amputations!12% amputation rate***15% amputation rate, 3 deaths@37 amputations or 12.1%#30% amputation rate
Nor is the high incidence of deaths and amputations from penetrating wounds only for combat injuries. Treatment of trauma also is important in the civilian arena. At one Level I civilian trauma center in Virginia, from 1995 to 1999, of 66 patients with penetrating extremity vascular injuries, there were five deaths from hemorrhagic shock. Trauma is the most frequent cause of death in the United States in persons under the age of 34. Because trauma occurs most in young people, trauma is the leading cause of life years lost. Up to 80% of all early trauma deaths are from uncontrolled hemorrhage. Each year in the United States, 1 in 100 people will visit an emergency room; 1 in 1000 people will be admitted and transfused; 1 in 3000 will die of trauma. About 50% of civilian deaths due to trauma are secondary to hemorrhage.
Currently available modalities for treating high pressure bleeding include tourniquets, fibrin glue, etc. However, these current bleeding treatments have significant disadvantages, such as nerve damage, limb ischemia, increased risk of amputation, etc.
Tourniquets were described more than two millenia (2000 years) ago as an adjuvant to surgical amputation. L. Zimmerman, I. Veith, Great Ideas in the History of Surgery, San Francisco, Calif.: Norman Publishing (1993), 31. Since then, tourniquets have become a primary a primary initial treatment for injuries associated with high pressure bleeding. Unfortunately, tourniquet use is associated with a variety of complications and difficulties including nerve damage, post-tourniquet syndrome, limb ischemia (distal ischemia), compartment syndromes, pulmonary embolus, increased risk of amputation, and limb wastage. A. K. Palmer, “Complications from tourniquet use,” Hand Clinics, 2:301-5 (1986); A. S. Estrera, R. P. King, M. R. Platt, “Massive pulmonary embolism: a complication of the technique of tourniquet ischemia,” J Trauma, 22:60-2 (1982). To decrease these risks, tourniquets must be intermittently loosened. This typically restarts the bleeding and is difficult for treating personnel to accomplish. Despite the potential complications and drawbacks, recent combat (such as the 1991-92 Croatian conflict) has verified the ability of tourniquets to delay shock in lower extremity arterial injuries. Z Lovric, V Lehner, B Wertheimer, L Kosic-Lovric, “Tourniquet occlusion technique for lower extremity artery reconstruction in war wound,” J Cardiovasc Surg (Torino), 38:153-5 (1997).
While fibrin products (such as fibrin glue, fibrin sealant and dry fibrin dressing) have been developed and shown to be effective in stopping venous bleeding, such fibrin products do have drawbacks. Fibrin products have had a tendency to be washed from the wound during high pressure bleeding, relative high cost. Some fibrin products put the patient at risk of viral exposure. Virally inactivated fibrin sealant has been developed, and is being used as an adjuvant to multiple types of surgery. C J Dunn, K L Goa, “Fibrin sealant: a review of its use in surgery and endoscopy,” Drugs, 58:863-86 (1999); M R Jackson, B M Alving, “Fibrin sealant in preclinical and clinical studies,” Curr Opin Hematol, 6:415-9 (1999). Fibrin glue has been shown to be effective in speeding hemostasis along vascular graft suture lines. A A Milne, W G Murphy, S J Reading, C V Ruckley, “A randomised trial of fibrin sealant in peripheral vascular surgery,” Vox Sang, 70:210-2 (1996). Fibrin glue has been tested as an adjuvant to surgery in the treatment of complex hepatic injury. S M Cohn, J H Cross, M E Ivy, A J Feinstein, M A Samotowka, “Fibrin glue terminates massive bleeding after complex hepatic injury,” J Trauma, 45:666-72 (1998). Formulations of fibrinogen and thrombin containing dressings, and dry fibrin sealant dressings have been proposed and studied in pig models of vascular injury and grade V liver injury. M J Larson, J C Bowersox, R C Lim, Jr., J R Hess, “Efficacy of a fibrin hemostatic bandage in controlling hemorrhage from experimental arterial injuries,” Arch Surg, 130:420-2 (1995); J B Holcomb, A E Pusateri, R A Harris, N C Charles, R R Gomez, J P Cole, L D Beall, V Bayer, M J MacPhee, J R Hess, “Effect of dry fibrin sealant dressings versus gauze packing on blood loss in grade V liver injuries in resuscitated swine,” J Trauma, 46:49-57 (1999); J B Holcomb, A E Pusater, R A Harris, T J Reid, L D Beall, J R Hess, M J MacPhee, “Dry fibrin sealant dressing reduce blood loss, resuscitation volume, and improve survival in hypothermic coagulopathic swine with grade V liver injuries,” J Trauma, 47:233-40 (1999). Dry fibrin sealant dressing was recently shown to be more effective than standard gauze in decreasing bleeding and maintaining blood pressure in ballistic injury. J Holcomb, M MacPhee, S Hetz, R Harris, A Pusateri “Efficacy of a dry fibrin sealant dressing for hemorrhage control after ballistic injury,” Arch Surg, 133:32-5 (1998).
While the development of “dry” products has increased their potential as alternatives to tourniquets for battlefield treatment, several potential problems remain. First, these products are relatively expensive because they are made from human blood (requiring a large amount of starting materials and multiple purification processes). Second, although virally inactivated, the fibrinogen contained in the products comes from multiple human donors and cannot be considered totally safe in terms of viral transmission. Third, these products must be held in place until bleeding stops or the material may simply wash out of the wound. The wash-out problem is especially seen when the bleeding is brisk as with arterial involvement.
Thrombin-mediated polymerization of fibrinogen has been the staple of hemostat technology for decades. “Hemostatic” means anything with the ability to enhance, speed or support blood clotting. Indeed, a recent patent dealing with hemostat systems still focuses on this process. J J Prior, D G Wallace, D H Sierra, F A DeLustro, “Compositions containing thrombin and microfibrillar nanometer collagen, and methods for preparation and use thereof,” U.S. Pat. No. 6,096,309 (2000).
Also, treatment of bleeding external wounds also has not progressed much, with conventional treatments not offering much beyond simply covering the wound. Most conventional dressings do little or nothing to promote hemostatis, prevent infection or relieve pain. Current bandages do little more than cover the wound and absorb fluids. There are emerging products that aid in hemostasis (fibrin glue, fibrin sealant, dry fibrin, kitosan, etc.) but most are quite expensive and some carry a risk of viral infection.
Another difficulty of conventional treatments for bleeding is that the patient loses much of his or her own blood, and transfusion is needed. Blood transfusion suffers from availability problems, purity concerns, etc., and is expensive. Costs of civilian blood transfusion for trauma were about $½ billion in 1997.
None of the current technologies adequately address the problem of treating high pressure arterial bleeding. A tourniquet alternative that is effective, inexpensive, lacks viral risk, and can be easily administered (such as by an army medic) would be a medical advance. A solution is still sought to the problem of assuring hemostatis and homeostasis for a penetrating injury (such as high-pressure bleeding combat wound) until the patient (such as a soldier) can reach a hospital facility for definitive care. Additionally, better treatment of bleeding external wounds is timely. Overall, better treatment of hemorrhage by the first responder would save lives, money and limbs, in military and civilian situations.